review article the relationship between type 2 diabetes … · 2019. 7. 31. · tion of glucose...

Hindawi Publishing CorporationJournal of Diabetes ResearchVolume 2013 Article ID 390534 9 pageshttpdxdoiorg1011552013390534

Review ArticleThe Relationship between Type 2 Diabetes Mellitusand Related Thyroid Diseases

Chaoxun Wang

Department of Endocrinology Shanghai Pudong Hospital Fudan University Pudong Medical Center 2800 Gongwei RoadHuinan Town Pudong Shanghai 201399 China

Correspondence should be addressed to Chaoxun Wang xunshdongerhotmailcom

Received 20 January 2013 Accepted 15 March 2013

Academic Editor Ake Lernmark

Copyright copy 2013 Chaoxun Wang This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Type 2 diabetes mellitus (T2DM) has an intersecting underlying pathology with thyroid dysfunction The literature is punctuatedwith evidence indicating a contribution of abnormalities of thyroid hormones to type 2 DM The most probable mechanismleading to T2DM in thyroid dysfunction could be attributed to perturbed genetic expression of a constellation of genes along withphysiological aberrations leading to impaired glucose utilization and disposal inmuscles overproduction of hepatic glucose outputand enhanced absorption of splanchnic glucose These factors contribute to insulin resistance Insulin resistance is also associatedwith thyroid dysfunction Hyper- and hypothyroidism have been associated with insulin resistance which has been reported to bethe major cause of impaired glucose metabolism in T2DM The state-of-art evidence suggests a pivotal role of insulin resistancein underlining the relation between T2DM and thyroid dysfunction A plethora of preclinical molecular and clinical studies haveevidenced an undeniable role of thyroid malfunctioning as a comorbid disorder of T2DM It has been investigated that specificallydesigned thyroid hormone analogues can be looked upon as the potential therapeutic strategies to alleviate diabetes obesity andatherosclerosis These molecules are in final stages of preclinical and clinical evaluation and may pave the way to unveil a distinctclass of drugs to treat metabolic disorders

1 Introduction

The role of hyperthyroidism in diabetes was investigated in1927 by Coller and Huggins proving the association of hy-perthyroidism and worsening of diabetes It was shown thatsurgical removal of parts of thyroid gland had an ameliorativeeffect on the restoration of glucose tolerance in hyperthyroidpatients suffering from coexisting diabetes [1]

There is a deep underlying relation between diabetes mel-litus and thyroid dysfunction [2] A plethora of studies haveevidenced an array of complex intertwining biochemical ge-netic and hormonal malfunctions mirroring this pathophys-iological association [2 3] 51015840 adenosine monophosphate-activated protein kinase (AMPK) is a central target formodu-lation of insulin sensitivity and feedback of thyroid hormonesassociated with appetite and energy expenditure [3] Hypo-thyroidism (Hashimotorsquos thyroiditis) or thyroid over activity(Gravesrsquo disease) has been investigated to be associated withdiabetes mellitus A meta-analysis reported a frequency of

11 in thyroid dysfunction in the patients of diabetes mellitus[4] Autoimmunity has been implicated to be the major causeof thyroid-dysfunction associated diabetes mellitus [5ndash7]

Unmanaged pro diabetes both type 1 and type 2 mayinduce a ldquolow T3 staterdquo characterized by low serum total andfree T3 levels increase in reverse T3 (rT3) but near normalserum T4 and TSH concentrations [8] The relation betweenT2DMand thyroid dysfunction has been a less explored arenawhich may behold answers to various facts of metabolic syn-drome including atherosclerosis hypertension and relatedcardiovascular disorders

T2DMowes its pathological origin to inappropriate secre-tion of insulin due to defective islet cell function or beta cellmass Continuous consumption of calories-rich meals junkfood and sedentary lifestyle have culminated into an epidem-ic of diabetes projected to afflict around 300 million peopleacross the globe by 2020 [9] Defective insulin secretion leadsto various metabolic aberrations in T2DM spanning fromhyperglycemia due to defective insulin-stimulated glucose

2 Journal of Diabetes Research

uptake and upregulated hepatic glucose production alongwith dyslipidaemia which includes impaired homeostasis offatty acids triglycerides and lipoproteins [10]

2 Epidemiology

Thyroid dysfunction is a common endocrine disorder withvariable prevalence Wickham survey reveals that a preva-lence of thyroid dysfunction in male adults in England was66 [11] According to Colorado prevalence study 95 ofparticipants were found to have elevated thyroid-stimulatinghormone (TSH) while 22 had a low TSH Accordingto the National Health and Nutrition Examination Survey(NHANES III Study) hypothyroidism and hyperthyroidismwere reported in 46 and 13 of the total participants[12] respectively The prevalence of thyroid dysfunction isadvancing with age all over the world and frequency ofprevalence was higher in women than men The prevalenceof subclinical hypothyroidism is reported to be about 4 to 85percent and may be as high as 20 percent in women olderthan 60 years The prevalence of subclinical hyperthyroidismis reported to be approximately 2

The prevalence of thyroid disorder in diabetic populationwas reported to be 134 with higher prevalence (314) infemale T2DM patients as compared to (69) in male T2DMpatients [13]The prevalence of thyroid dysfunction in T2DMpatients was reported to be 123 in Greece and 16 in SaudiArabia byAkbar et al [14] Considerably T2DMpatientsweremore prone to thyroid disorders

3 Peripheral Effects of Thyroid Hormones onInsulin Secretion and Sensitivity

Thyroid hormones directly control insulin secretion In hy-pothyroidism there is a reduction in glucose-induced insulinsecretion by beta cells and the response of beta cells toglucose or catecholamine is increased in hyperthyroidismdueto increased beta cell mass Moreover insulin clearance isincreased in thyrotoxicosis [15 16]

31 Thyrotoxicosis Increased glucose output from liver is thepivotal reason for the induction of hyperinsulinaemia induc-tion of glucose intolerance and development of peripheralinsulin resistance [17] Glucose tolerance in thyrotoxicosis iscaused by elevated hepatic glucose output along with upregu-lated glycogenolysis [2] This phenomenon is responsible forworsening of subclinical diabetes and exaggeration of hyper-glycaemia in T2DMThyrotoxicosis may lead to ketoacidosisalso due to elevated lipolytic actions and increased hepatic120573 oxidation [18 19] This phenomenon has been shown inFigure 1

32 Hypothyroidism Reduced glucose absorption from gas-trointestinal tract accompanied by prolonged peripheral glu-cose accumulation gluconeogenesis diminished hepatic glu-cose output and reduced disposal of glucose are hallmarks ofhypothyroidism [20] In overt or subclinical hypothyroidism

Hyperthyroidism

LipolysisGLUT 2 on liver

Lactateproduction

Hyperglycemia

Nonoxidativeglucose disposal

Free fattyacids

Hepaticglucoseoutput

Figure 1The relation between hyperthyroidism and hyperglycemiavia lipid metabolism oxidative stress and hepatic dysfunction

Hyperthyroidism

Reduced insulin synthesis

Decreased

Delayedgluconeogenesis

Decreasedglucose disposal

hepaticglucoseoutput

Hypoglycemia

Impaired glucoseabsorption

Figure 2 The relation between hypothyroidism and hypoglycemiamediated by reduced insulin synthesis and impaired hepatic glucoseoutput

insulin resistance leads to glucose-stimulated insulin secre-tion [2] In subclinical hypothyroidism diminished rate ofinsulin stimulated glucose transport rate caused by perturbedexpression of glucose transporter type 2 gene (GLUT 2)translocation may lead to insulin resistance Moreover dueto reduced renal clearance of insulin in hypothyroid condi-tions physiological requirements of insulin were diminishedAnorectic conditions in hypothyroidism may also contributeto reduced insulin in this state An enhanced dose of insulinis required to ameliorate hypothyroidism but the therapywarrants caution for adrenal or pituitary failure [21] Thisphenomenon has been shown in Figure 2

Journal of Diabetes Research 3

4 Relation between the Pathological FeaturesExhibited in Hyperthyroidism and T2DMRole of Insulin Resistance and Other Factors

The pathological features of T2DM include increased intesti-nal glucose absorption reduced insulin secretion and changein the 120573-cell mass [22] Further symptoms also includeincreased insulin degradation [23] increased glucagon secre-tion [24] increased hepatic glucose production [24] en-hanced catecholamines and insulin resistance [25] Thesefactors have been investigated to be an integral part of hyper-thyroidism as well [26] Hence an intersection of patholog-ical basis occurs which gives us cue to an array of physio-logical aberrations which are common in hyperthyroidismand T2DM Among the above-mentioned symptomatologyinsulin resistance has been the most important facet con-necting thyroid dysfunction and T2DM Insulin resistance isa condition which occurs in both hypothyroidism and hy-perthyroidism [27]

Insulin resistance in the muscles and liver is a character-istic feature of T2DM An undisturbed glucose homeostasisand intact insulin secretary response and unperturbed sensi-tivity of the tissues to insulin are essential tomaintain normalblood glucose levels [28ndash31]

Glucose disposal is mediated by the conjoint effect ofinsulin and hyperglycemia to modulate three basic phenom-enon Firstly diminution of endogeneous (hepatic) glucoseproduction Secondarily enhanced uptake of glucose (hepaticand splanchnic) Thirdly upregulation of glucose by periph-eral tissues (skeletal muscles) Glucose uptake into musclesis modulated by glycolysis and glycogen synthesis Hepaticinsulin resistance is characterized by glucose overproductioninspite of fasting hyperinsulinemia and enhanced rate ofhepatic glucose outputwas the pivotalmodulator of increasedfasting plasma glucose (FPG) concentration in T2DM sub-jects [24] In insulin resistance in the postabsorptive statemuscle glucose is upregulated but the efficiency of uptakeis reduced In the wake of such conditions reduced glucoseuptake into themuscles and enhanced hepatic glucose outputlead to worsening of glucose metabolism

The term harmonious quartet is used to address the corepathology of insulin resistance [24] Deregulated glucosedisposal and metabolism in adipocytes muscles and liveralong with impaired insulin secretion by the pancreatic betacells constitute the four major organ system abnormalitieswhich play a definitive role in the pathogenesis of T2DM It isworth considering that insulin resistance has been a provencondition in hyperthyroidism as well as hypothyroidismInsulin resistance also leads to impaired lipid metabolism ac-cording to recent findings [32] Hence it appears that insulinresistance is the possible link between T2DM and thyroiddysfunction

Insulin resistance and 120573 cell function are inversely cor-related with thyroid stimulating hormone which may beexplained by insulin-antagonistic effects of thyroid hormonesalongwith an increase in TSHThehigher serumTSHusuallycorresponds to lower thyroid hormones via negative feedbackmechanism As TSH increased thyroid hormones decreased

and insulin antagonistic effects are weakenedThese observa-tions demonstrate that insulin imbalance is closely associatedwith thyroid dysfunction and the phenomenon id mediatedvia 120573 cell dysfunction [33]

41 Association of Insulin Resistance in Hyperthyroidismand Subclinical Hyperthyroidism Hyperthyroidism has beenassociated with insulin resistance which has been linkedwith elevated glucose turnover increased intestinal glucoseabsorption elevated hepatic glucose output increased freefatty acid concentrations increased fasting and or postpran-dial insulin an proinsulin levels and increased peripheralglucose transport accompanied by glucose utilization [2734] T2DM patients with thyroid dysfunction have beenproven to be more susceptible to ketosis [35] and ketogenesis[36] Insulin resistance has been shown to be associatedwith subclinical hypothyroidism which is in turn linked toimpaired lipid balance and risk of development of metabolicsyndrome [37ndash39]

411 Role of Liver In hyperthyroidism endogenous glucoseproduction is elevated and reduces hepatic insulin sensitivityin humans [40] due to glycogenesis and glycogenolysis Therole of hypothalamus mediated sympathetic action in liverhas been proposed [41] along with increased expressionof GLUT 2 transporters in liver which ultimately lead toelevation in plasma free fatty acid [42 43]

412 Role ofMuscles There ismarked increase in the skeletalglucose utilization in hyperthyroid state [34] Increased glu-cose utilization has been reported to be mediated by insulinstimulated glucose oxidation rates [44ndash46] Under such con-ditions reduced glyco genesis has been reported due to insu-lin stimulated nonoxidative glucose disposal which is accom-panied by redirection of intracellular glucose towards glycol-ysis and lactate formation [27] The transport of lactate fromperiphery to liver leads to enhanced production of glucosevia Corirsquos cycle Hyperthyroidism has also been associatedwith enhanced insulin sensitivity [47] Increased peripheralinsulin resistance has been coupled with elevated expressionof bioactive inflammatory mediators including adipokines(IL-6 and TNF-alpha) [16] which lead to insulin resistance

413 Role of Fat Tissues Haluzik et al summarized that rateof local lipolysis in the abdominal subcutaneous adipose tis-sue was a result of modulation of norepinephrine (NE) levelsand adrenergic postreceptor signaling by thyroid hormones[48]Other studies reported that thyroid hormones are neces-sary for the mobilization of the tissue lipids especially brownadipose tissues (BATs)which are the fuel for the production ofheat [49] Hypothyroidism and decreased thyroid hormonelevel are responsible for decreased thermogenesis in BATS14 and lipogenesis are important factors for thermogenesismediated by thyroid hormone [50]

42 Association of Insulin Resistance in Hypothyroidismand Subclinical Hypothyroidism Insulin resistance has beenshown to be caused in hypothyroidism in various in vitro and


preclinical studies [51ndash53] where it was found that peripheralmuscles became less responsive in hypothyroid conditionsA possible role of dysregulated metabolism of leptin hasbeen implicated for such pathology [53] A direct relationbetween hypothyroidism and insulin resistance has beendemonstrated by various authors [15 54ndash56]

Subclinical hypothyroidism has been reported to beassociated with insulin resistance [55 57 58] Howeverconflicting findings have also been reported by other workers[59 60] indicating the need of further investigations in thisdomain

5 Genetic Causes of T2DM and ThyroidDysfunction The Possible Intersection

51 Effect ofThyroid Hormones on the LiverThe Role of GenesVarious genes have been identified which are identified withgluconeogenesis glycogenmetabolism and insulin signalingThese include glucose 6 phosphate protein kinase B (Akt2)1205732adrenergic receptor inhibitory G protein (Gi) phos-

phoenolpyruvate kinase (PEPCK) [25] pyruvate carboxylase(PC) GLUT 2 [42 64] malic enzyme [65] and carbohydrateresponse element binding protein (ChREBP) [66] A raisedhepatic expression of GLUT 2 in hyperthyroid rats was ob-served as compared to hypothyroid rats [64]

Transcription of various enzymes involved in lipid me-tabolism has been reported to increase in hyperinsulinemicor insulin-resistant mice [2 67] Transcriptional activation ofmalic acid has proven to be involved in fatty acid synthesis[68]

52 Effect of Thyroid Hormones on the Skeletal Muscle Thevarious genes which influence the interaction of thyroidhormone and skeletal muscles include GLUT1 GLUT4 [64]1205732adrenergic receptors [69] phosphoglycerate kinase (PGK)

[70] PPAR gamma coactivator-1 alpha (PGC-1 alpha) [71]and mitochondrial uncoupling protein [72] Amongst thevarious genes identified GLUT-4 and UCP-3 have beenstudied in detail In the skeletal muscles GLUT 4 has beenproven to be mediated by the influence of T3 and it canelevate basal and insulin mediated transport of glucose [64]

Mitochondrial uncoupling protein 3 (UCP 3) is a recentlyidentified gene and has been unveiled to be associated withglucose metabolism and decreased fatty acid oxidation [73]It has also been reported to play a pivotal role in the downreg-ulated activation of AktPKB and 51015840 adenosine monophos-phate-activated protein kinase signaling [2 73] The role ofT2 has also been explored and it has been proven that it isassociated with sarcolemmal GLUT-4 Phosphofructokinaseand glycolytic enzymes have been associated with the T2-mediated GLUT 4 activity [74] A number of genes have beenassociated with peripheral glucose metabolism [2]

Autoimmune causes are reported to be responsible forthe genetic dysfunction in the diabetic patient suffering fromthyroid related disorders However these findings advocatean immense clinical evidence to support association betweenT1DM (Type 1 diabetes mellitus) and autoimmune thyroiddysfunction (AITD) [75 76] Arrays of genes involved in

metabolism of glucose are modulated by active thyroidhormone T3 by binding to the thyroid hormone receptorsThese receptors are derived from TR1205721 TR1205731 TR1205732 andTR1205733 These are four major T3 binding isoforms [77] TR1205721is hypothesized to regulate the metabolic effects of thyroidhormone TR1205731 and TR1205732 are related with maintenance ofhypothalamic-pituitary-thyroid axis and keeping the euthy-roid state [78]

It has been investigated that 353-triiodothyronine isderived from T4 It can be activated via removing an iodineatom from the phenolic ring by the iodothyronine deiodinas-es type 1 (D1) and type 2 (D2) Type 3 deiodinase (D3) inac-tivates thyroid hormone by removing an iodine atom fromthe tyrosyl ring The deiodinases are expressed in varioustissues and their expression levels vary enormously duringdevelopment and are regulated by thyroid hormone statusType deiodinase (D1) is expressed in liver while type 2 deiod-inase (D2) is expressed in adipose tissue and skeletal muscleThey are involved in regulation of bioavailability of T3 andhence the response to insulin Elevated concentrations ofT3 are associated novel missense variant (Thr92Ala) Thisphenomenon is closely associated with insulin resistance It isalso associated with a surge in glucose turnover accompaniedby an upregulation of insulin-mediated glucose disposal inskeletal muscle and adipose tissue

This phenomenon mediated via positive regulation ofinsulin sensitive GLUT-4 transcription [78 79] showed thatthere were profound genomic effects of T3 on hepatic glucosemetabolism TR expressed in the hepatocyte and stimulationof T3-sensitive neurons in the hypothalamus-modulatedhepatic glucose production via sympathetic projections to theliver are mediated by circulating glucoregulatory hormones[79] Recent findings have elucidated polymorphism of deio-dinase type 2 (DIO2) geneThr92Ala which suggest homozy-gosity for this polymorphism which in turn is responsible forenhanced risk of T2DM [80]

A separate meta-analysis indicated that intracellular tri-iodothyronine (T3) is responsible for aberrations in insulinsensitivity [4] It has also been reported that polymorphismofThr92Ala leads to a lower activity of type 2 deiodinase whichin turn is associated with insulin resistance The D2 gene hasa peculiar transcriptional and posttranslational regulation Itis a potential modulator of insulin action in skeletal muscleand adipose tissue through the regulation of theGLUT-4 genetranscription [81]

Investigations using skeletal muscles in hypothyroid andeuthyroid humans have revealed a discernable influenceon the downregulated expression of glucose transporter 5(GLUT 5) but not GLUT 4 [57 82] Glucose oxidationand glycogen synthesis are reduced in hypothyroidism [21]Simultaneous increase in the insulin sensitivity occurs whenthe levels of thyroid hormone were increased This phe-nomenon is governed by intracellular generation of T3 aspolymorphisms ofDIO2with reducedT3 generation and alsocontributes to insulin resistance [80] In hyperthyroidismthe expression of GLUT 2 is increased as compared toeuthyroid state [16] In such conditions perturbations inlipid metabolism further link TH to insulin resistance [16]Thyroid hormone causes elevation in the plasma fatty acid


Increasegluconeogenesis

Lipogenesis

Decrease glycogensynthesis

Increase glucoseoutput

G-6-P 1205732 Gi PC and PEPCK

Malic enzymeChREBP

Protein kinase B

Decreaseglycogensynthesis

Increase glucosetransport

Increaselipolysis

Increaseglycolysis

Increasemitochondrialfunction

GLUT 1 and 4

1205732-adrenoreceptor

PGK and HIF

PPAR-120574coactivator-UCP-3

Liver Peripheral tissues

1120572

1120572

Figure 3 Effect of thyroid hormones on the liver and peripheral tissues

levels in hyperthyroid conditions but not in hypothyroid con-ditions Low intracellular fatty acid levels are associated withhepatic insulin sensitivity via modulation of cellular insulinuptake or lipid oxidation [83] Fatty acid uptake mediatedby TH is a tissue-specific phenomenon and is upregulated inboth hypo and hyperthyroidism [79]

Thyrotoxicosis leads to enhanced lipid peroxidationwhereas hypothyroidism causes diminished glucose oxida-tion LDL clearance leads to lowered cholesterol and triglyc-eride levels TH instigates upregulation of catecholamineaction leading to lipolysis on adipocytes and enhancementof circulating FA Elevated supply of FA counteracts TH-mediated elevated hepatic long-chain FA oxidative processElevated circulating FA levels and availability of gluco-neogenic substrates from peripheral reserves reciprocatesincreased gluconeogenesis in T3-treated animals It has beenreported that T3 enhances fasting plasma glucose and free FAlevels Activation of peripheral substrates explains precipita-tion of hyperglycemia in thyrotoxicosis [84] Paradoxicallyhyperglycemic effect of thyrotoxicosis can be reversed byincreased blood supply to muscles providing a better supplyof substrate [16] This phenomenon is shown in Figure 3

6 Relation of Antidiabetic Therapy(Metformin) and Risk of ThyroidRelated Perturbations

Cappelli et al evaluated the thyroid hormone profile bystudying the interaction between metformin and circulatingthyroid function parameters in patients who were started onmetformin [85] A pilot study on diabetic hypothyroid patientrevealed baseline reduction of TSH level after 6 monthssimilarly a large cohort study on diabetic patients showedsignificant fall of TSH level in euthyroid patients on L-T4substitution and subclinical hypothyroid patientswhodidnotreceive LT4 treatment except in euthyroid patients after 1 yearonmetforminThis study concluded that TSH lowering effectof metformin only seen in untreated hypothyroid patientand with L-T4 replacement therapy irrespective of thyroid

function test Similar findings were reported by Vigerskyet al Cappelli et al and Chen et al [86ndash88]

In vitro studies support the use of metformin in otherthyroid diseases other than hypothyroidism Metformin hasinhibited the cell proliferation and growth-stimulatory effectof insulin on thyroid carcinoma cell lines Same study showedthe stimulation of apoptosis and enhancement in the actionof chemotherapeutic agents (doxorubicin and cisplatin) bymetformin [89] Other reports support growth inhibitoryeffect of metformin in mammalian cell lines mediated bymammalian target of Rapamycin (mTOR) and cyclin D1 [90]

7 Therapeutic Role of ThyroidHormone Analogues

Thyroid hormones have profound influence on various physi-ological processes ranging frommetabolism of lipid proteinand carbohydrate The literature is punctuated with reportsclaiming antiatherogenic and lipolytic influences of thyroidhormones However their deleterious effects on bone mus-cles and heart are major hurdles [91] Thyroid hormoneanalogues have paved the way for the development of novelstrategies in the treatment of atherosclerosis diabetes andobesity [91] Recent investigations and subsequent findingshave provided many cues that could behold trails of complexphysiological mechanisms in the endocrine crosstalk of gly-caemic surge and thyroid dysfunction [91]

Development of potent thyroid hormone analogues thatselectively elude the harmful effects of thyroid hormoneand at the same time produce desirable therapeutic effectshas been the cynosure of scientific research [92ndash94] Thethrust of the research has been in designing TH analogueswhich are devoid of the cardiac complications [27 95] Pre-clinical investigations have demonstrated that carbohydrateresponse element-binding protein (ChREBP) is the pivotaltranscription factor modulating the stimulation of hepaticlipogenesis mediated by glucose It is the primary target ofthyroid hormones in liver and white adipose tissues [66]ChREBP has been reported to be regulated by TR120573 only andnot TR120572 in liver and white adipose tissue [66]


Table 1 Diabetic practice guidelines for thyroid screening in patients with diabetes

Sr no Guidelines Type 2 diabetes Comments

(1) AmericanThyroid Association guidelinesfor detection of thyroid dysfunction [61]

Patients with diabetes may require morefrequent testing

Recommends TSH from 35 yrs and every5 yrs thereafter in all adults high riskpersons may require more frequent testsDiabetes mentioned as high-risk but doesnot distinguish between T1DM andT2DM

(2)American Association of ClinicalEndocrinologists Thyroid disease clinicalPractice guidelines 2002 [62]

Thyroid palpation and TSH at diagnosisand at regular intervals especially if goitreor other autoimmune disease presents

No specific recommendation for T2DM

(3)British Thyroid Association andAssociation of Clinical BiochemistryGuidelines 2006 [63]

TFT at baseline but routine annual TFT isnot recommended

TSH and antibodies are recommended indiabetic patients in pregnancy andpostpartum

8 Clinical Guidelines Governingthe Role of Detection of Thyroid Detectionin T2DM Patients

Various studies have been undertaken to understand the roleimportance and need of determination of thyroid dysfunc-tion in the patients of T2DM It has been unequivocallyapparent that testing for thyroid dysfunction in T2DM pa-tients is necessary and should be carried out annually [13]Guidelines for screening of thyroid in diabetes patients in UKand USA are presented in Table 1

TheldquoAmericanThyroidAssociationrdquoguidelines for T2DMpatients require frequent testing for thyroid dysfunctionThey recommend testing from 35 years of age and every5 years thereafter in adults High-risk patients may requiremore frequent testing The American Association of ClinicalEndocrinologists Thyroid Disease Clinical Practice Guide-lines (2002) recommends thyroid palpation and TSH indiagnosis especially if goitre or other autoimmune diseasepresents in association with T2DM Regular screening forthyroid abnormalities in all diabetic patients will allow earlytreatment of subclinical thyroid dysfunction A sensitiveserum TSH assay is the screening test of choice It has alsobeen proposed that in T2DM patients a TSH assay shouldbe performed at diagnosis and then repeated at least every 5years

9 Conclusion

In internal medicine it is repeatedly proven that the asso-ciation between thyroid dysfunction and diabetes mellitusis evident Thyroid dysfunction chiefly comprises hypothy-roidism and hyperthyroidism although the entity belongs tothe same organ but with vast difference in pathophysiologyas well as clinical picture The interface between thyroidmalfunction owing to diabetes is a matter of investigationThe literature suggests that polyendocrinal multidysfunctionleads to stimulation of a cascade of reactions which are actu-ally antihomeostatic in nature For instance hypoadrenalismas well as hypopituitarism exhibits strong linkage with hypo-thyroidism and consequently diabetes mellitus

Recent findings have evidenced the intricate bond be-tween subclinical hypothyroidism and diabetes mellitus thatdeceptively contribute to themajor complications such as ret-inopathy and neuropathy Cardiovascular events and micro-or macro-angiopathies are the counterreflection of resur-gence of heavily disturbed lipid metabolism due to thyroiddyscrasias It is also evident from the existing literature thatinsulin resistance bears an indispensable role in connectingT2DMand thyroid dysfunction Novelmolecules have shownthe path for the development of suitable thyroid hormonereceptor analogues to treat metabolic diseases It is importantto diagnose thyroid dysfunction in T2DM patients andthis practice should be inculcated in clinical settings withimmediate effect to nourish further understanding of thyroiddysfunction and T2DM

Conflict of Interests

The author declares that he has no conflict of interests

Authorsrsquo Contributions

Themain author contributed fully to the review

Acknowledgment

The author would like to thank BioQuest Solutions forproviding editorial services for this review

References

[1] F A Coller and C B Huggins ldquoEffect of hyperthyroidism upondiabetes mellitus striking improvement in diabetes mellitusfrom thyroidectomyrdquo Annals of Surgery vol 86 no 6 pp 877ndash884 1927

[2] G Brenta S Danzi and I Klein ldquoPotential therapeutic appli-cations of thyroid hormone analogsrdquo Nature Clinical PracticeEndocrinology and Metabolism vol 3 no 9 pp 632ndash640 2007

[3] F Goglia M Moreno and A Lanni ldquoAction of thyroid hor-mones at the cellular level the mitochondrial targetrdquo FEBSLetters vol 452 no 3 pp 115ndash120 1999


[4] R Kadiyala R Peter andO EOkosieme ldquoThyroid dysfunctionin patients with diabetes clinical implications and screeningstrategiesrdquo International Journal of Clinical Practice vol 64 no8 pp 1130ndash1139 2010

[5] O Kordonouri A M Maguire M Knip et al ldquoOther com-plications and associated conditions with diabetes in childrenand adolescentsrdquo Pediatric Diabetes vol 10 no 12 pp 204ndash2102009

[6] R W Holl B Bohm U Loos M Grabert E Heinze and JHomoki ldquoThyroid autoimmunity in children and adolescentswith type 1 diabetes mellitus Effect of age gender and HLAtyperdquo Hormone Research vol 52 no 3 pp 113ndash118 1999

[7] J M Barker J Yu L Yu et al ldquoAutoantibody rdquosubspecificityrdquo intype 1 diabetes risk for organ-specific autoimmunity clusters indistinct groupsrdquoDiabetes Care vol 28 no 4 pp 850ndash855 2005

[8] J EDonckier ldquoEndocrine diseases anddiabetesrdquo inText Book ofDiabetes Mellitus J C Pickup and GWilliams Eds vol 27 pp21ndash27 Blackwell Publishing Company Chichester UK 2003

[9] J D Baxter W H Dillmann B L West et al ldquoSelectivemodulation of thyroid hormone receptor actionrdquo Journal ofSteroid Biochemistry and Molecular Biology vol 76 no 1ndash5 pp31ndash42 2001

[10] J D Baxter and PWebb ldquoThyroid hormonemimetics potentialapplications in atherosclerosis obesity and type 2 diabetesrdquoNature Reviews Drug Discovery vol 8 no 4 pp 308ndash320 2009

[11] WMG Tunbridge D C Evered andRHall ldquoThe spectrumofthyroid disease in a community theWhickham surveyrdquoClinicalEndocrinology vol 7 no 6 pp 481ndash493 1977

[12] J G Hollowell N W Staehling W D Flanders et al ldquoSerumTSH T4 and thyroid antibodies in theUnited States population(1988 to 1994) National Health and Nutrition ExaminationSurvey (NHANES III)rdquo Journal of Clinical Endocrinology andMetabolism vol 87 no 2 pp 489ndash499 2002

[13] P Perros R J McCrimmon G Shaw and B M Frier ldquoFre-quency of thyroid dysfunction in diabetic patients value ofannual screeningrdquoDiabetic Medicine vol 12 no 7 pp 622ndash6271995

[14] D H Akbar M M Ahmed and J Al-Mughales ldquoThyroid dys-function and thyroid autoimmunity in Saudi type 2 diabeticsrdquoActa Diabetologica vol 43 no 1 pp 14ndash18 2006

[15] S Stanicka K Vondra T Pelikanova P Vlcek M Hill and VZamrazil ldquoInsulin sensitivity and counter-regulatory hormonesin hypothyroidism and during thyroid hormone replacementtherapyrdquo Clinical Chemistry and Laboratory Medicine vol 43no 7 pp 715ndash720 2005

[16] P Mitrou S A Raptis and G Dimitriadis ldquoInsulin action inhyperthyroidism a focus on muscle and adipose tissuerdquo Endo-crine Reviews vol 31 no 5 pp 663ndash679 2010

[17] V Lambadiari P Mitrou E Maratou et al ldquoThyroid hormonesare positively associated with insulin resistance early in thedevelopment of type 2 diabetesrdquo Endocrine vol 39 no 1 pp28ndash32 2011

[18] M Potenza M A Via and R T Yanagisawa ldquoExcess thyroidhormone and carbohydrate metabolismrdquo Endocrine Practicevol 15 no 3 pp 254ndash262 2009

[19] M S Eledrisi M S Alshanti M F Shah B Brolosy and NJaha ldquoOverview of the diagnosis and management of diabeticketoacidosisrdquoAmerican Journal of the Medical Sciences vol 331no 5 pp 243ndash251 2006

[20] T L Althausen andM Stockholm ldquoThe influence of the thyroidgland on absorption in the digestive tractrdquoThe American Jour-nal of Physiology vol 123 no 3 pp 577ndash588 1938

[21] L H Duntas J Orgiazzi and G Brabant ldquoThe interfacebetween thyroid and diabetes mellitusrdquo Clinical Endocrinologyvol 75 no 1 pp 1ndash9 2011

[22] A Clark L C Jones E de Koning B C Hansen and D RMatthews ldquoDecreased insulin secretion in type 2 diabetes aproblem of cellular mass or functionrdquo Diabetes vol 50 no 1pp S169ndashS171 2001

[23] J P Randin B Scazziga E Jequier and J P Felber ldquoStudy ofglucose and lipid metabolism by continuous indirect calorime-try in Gravesrsquo disease effect of an oral glucose loadrdquo Journal ofClinical Endocrinology and Metabolism vol 61 no 6 pp 1165ndash1171 1985

[24] R A DeFronzo ldquoPathogenesis of type 2 diabetes mellitusrdquoMedical Clinics of North America vol 88 no 4 pp 787ndash8352004

[25] D M Muoio and C B Newgard ldquoMechanisms of diseasemolecular and metabolic mechanisms of insulin resistance and120573-cell failure in type 2 diabetesrdquo Nature Reviews Molecular CellBiology vol 9 no 3 pp 193ndash205 2008

[26] G Dimitriadis P Mitrou V Lambadiari et al ldquoInsulin-stimu-lated rates of glucose uptake in muscle in hyperthyroidism theimportance of blood flowrdquo Journal of Clinical Endocrinology andMetabolism vol 93 no 6 pp 2413ndash2415 2008

[27] G Brenta F S Celi M Pisarev M Schnitman I Sinay andP Arias ldquoAcute thyroid hormone withdrawal in athyreoticpatients results in a state of insulin resistancerdquoThyroid vol 19no 6 pp 665ndash669 2009

[28] R A DeFronzo R Gunnarsson and O Bjorkman ldquoEffects ofinsulin on peripheral and splanchnic glucose metabolism innoninsulin-dependent (type II) diabetes mellitusrdquo Journal ofClinical Investigation vol 76 no 1 pp 149ndash155 1985

[29] R A DeFronzo ldquoPathogenesis of type 2 diabetes metabolic andmolecular implications for identifying diabetes genesrdquoDiabetesReviews vol 5 no 3 pp 177ndash269 1997

[30] AMari JWahren R ADeFronzo and E Ferrannini ldquoGlucoseabsorption and production following oral glucose compari-son of compartmental and arteriovenous-difference methodsrdquoMetabolism Clinical and Experimental vol 43 no 11 pp 1419ndash1425 1994

[31] L Mandarino R Bonadonna O McGuinness and D Wasser-man ldquoRegulation of muscle glucose uptake in vivordquo in Hand-book of Physiology The Endocrine System The Endocrine Pan-creas and Regulation of Metabolism L S Jefferson and A DCherrington Eds vol 2 pp 803ndash848 Oxford University PressOxford UK 2001

[32] K B Kapadia P A Bhatt and J S Shah ldquoAssociation betweenaltered thyroid state and insulin resistancerdquo Journal of Pharma-cology and Pharmacotherapeutics vol 3 pp 156ndash160 2012

[33] G Chen J Wu Y Lin et al ldquoAssociations between cardiovas-cular risk insulin resistance 120573-cell function and thyroid dys-function a cross-sectional study in She ethnicminority groupofFujian Province in Chinardquo European Journal of Endocrinologyvol 163 no 5 pp 775ndash782 2010

[34] G D Dimitriadis and S A Raptis ldquoThyroid hormone excessand glucose intolerancerdquo Experimental and Clinical Endocrinol-ogy and Diabetes vol 109 no 2 pp S225ndashS239 2001

[35] M Beylot J P Riou F Bienvenu and R Mornex ldquoIncreasedketonaemia in hyperthyroidism Evidence for a 120573-adrenergicmechanismrdquo Diabetologia vol 19 no 6 pp 505ndash510 1980

[36] M Beylot ldquoRegulation of in vivo ketogenesis role of free fattyacids and control by epinephrine thyroid hormones insulin


and glucagonrdquoDiabetes andMetabolism vol 22 no 5 pp 299ndash304 1996

[37] J Rezzonico H Niepomniszcze M Rezzonico E Pusiol MAlberto and G Brenta ldquoThe association of insulin resistancewith subclinical thyrotoxicosisrdquoThyroid vol 21 no 9 pp 945ndash949 2011

[38] M Peppa G Betsi and G Dimitriadis ldquoLipid abnormalitiesand cardiometabolic risk in patients with overt and subclinicalthyroid diseaserdquo Journal of Lipids vol 2011 Article ID 5758409 pages 2011

[39] C C Wang and J E B Reusch ldquoDiabetes and cardiovasculardisease changing the focus from glycemic control to improvinglong-term survivalrdquo The American Journal of Cardiology vol110 no 9 pp 58Bndash68B 2012

[40] P Cavallo-Perin A Bruno L Boine M Cassader G Lenti andG Pagano ldquoInsulin resistance in Gravesrsquo disease a quantitativein-vivo evaluationrdquo European Journal of Clinical Investigationvol 18 no 6 pp 607ndash613 1988

[41] L P Klieverik C P Coomans E Endert et al ldquoThyroidhormone effects on whole-body energy homeostasis and tissue-specific fatty acid uptake in vivordquo Endocrinology vol 150 no 12pp 5639ndash5648 2009

[42] S P Weinstein E OrsquoBoyle M Fisher and R S HaberldquoRegulation of GLUT2 glucose transporter expression in liverby thyroid hormone evidence for hormonal regulation of thehepatic glucose transport systemrdquo Endocrinology vol 135 no2 pp 649ndash654 1994

[43] TMokunoKUchimura RHayashi et al ldquoGlucose transporter2 concentrations in hyper- and hypothyroid rat liversrdquo Journalof Endocrinology vol 160 no 2 pp 285ndash289 1999

[44] G Dimitriadis B Baker H Marsh et al ldquoEffect of thyroidhormone excess on action secretion andmetabolism of insulinin humansrdquoTheAmerican Journal of Physiology vol 248 no 5pp E593ndash601 1985

[45] A J McCulloch D G Johnston and P H Baylis ldquoEvidencethat thyroid hormones regulate gluconeogenesis from glycerolin manrdquo Clinical Endocrinology vol 19 no 1 pp 67ndash76 1983

[46] M C Foss G M G F Paccola M J A Saad W P Pimenta CE Piccinato and N Iazigi ldquoPeripheral glucose metabolism inhuman hyperthyroidismrdquo Journal of Clinical Endocrinology andMetabolism vol 70 no 4 pp 1167ndash1172 1990

[47] D C ShenM B Davidson SW Kuo andWH Sheu ldquoPeriph-eral and hepatic insulin antagonism in hyperthyroidismrdquo Jour-nal of Clinical Endocrinology and Metabolism vol 66 no 3 pp565ndash569 1988

[48] M Haluzik J Nedvidkova V Bartak et al ldquoEffects of hypo andhyperthyroidism on noradrenergic activity and glycerol con-centrations in human subcutaneous abdominal adipose tissueassessed with microdialysisrdquo Journal of Clinical Endocrinologyand Metabolism vol 88 no 12 pp 5605ndash5608 2003

[49] G Mory D Ricquier P Pesquies and P Hemon ldquoEffects ofhypothyroidism on the brown adipose tissue of adult ratscomparison with the effects of adaptation to coldrdquo Journal ofEndocrinology vol 91 no 3 pp 515ndash524 1981

[50] H C Freake and J H Oppenheimer ldquoStimulation and S14mRNAand lipogenesis in brown fat by hypothyroidism coldexposure and cafeteria feeding evidence supporting a generalrole for S14 in lipogenesis and lipogenesis in themaintenance ofthermogenesisrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 84 no 9 pp 3070ndash30741987

[51] G Dimitriadis M Parry-Billings S Bevan et al ldquoThe effectsof insulin on transport and metabolism of glucose in skeletalmuscle from hyperthyroid and hypothyroid ratsrdquo EuropeanJournal of Clinical Investigation vol 27 no 6 pp 475ndash483 1997

[52] A Dubaniewicz H Kaciuba-Uscilko K Nazar and L Budo-hoski ldquoSensitivity of the soleus muscle to insulin in resting andexercising rats with experimental hypo- and hyper-thyroidismrdquoBiochemical Journal vol 263 no 1 pp 243ndash247 1989

[53] P Cettour-Rose C Theander-Carrillo C Asensio et alldquoHypothyroidism in rats decreases peripheral glucose utilisa-tion a defect partially corrected by central leptin infusionrdquoDiabetologia vol 48 no 4 pp 624ndash633 2005

[54] C Rochon I Tauveron C Dejax et al ldquoResponse of glucosedisposal to hyperinsulinaemia in human hypothyroidism andhyperthyroidismrdquoClinical Science vol 104 no 1 pp 7ndash15 2003

[55] A Handisurya G Pacini A Tura A Gessl and A Kautzky-Willer ldquoEffects of T4 replacement therapy on glucose metabo-lism in subjects with subclinical (SH) and overt hypothyroidism(OH)rdquo Clinical Endocrinology vol 69 no 6 pp 963ndash969 2008

[56] G Dimitriadis P Mitrou V Lambadiari et al ldquoInsulin actionin adipose tissue and muscle in hypothyroidismrdquo Journal ofClinical Endocrinology andMetabolism vol 91 no 12 pp 4930ndash4937 2006

[57] E Maratou D J Hadjidakis M Peppa et al ldquoStudies of insulinresistance in patientswith clinical and subclinical hyperthyroid-ismrdquo European Journal of Endocrinology vol 163 no 4 pp 625ndash630 2010

[58] P H Dessein B I Joffe and A E Stanwix ldquoSubclinicalhypothyroidism is associatedwith insulin resistance in rheuma-toid arthritisrdquoThyroid vol 14 no 6 pp 443ndash446 2004

[59] M Owecki E Nikisch and J Sowinski ldquoHypothyroidism hasno impact on insulin sensitivity assessed with HOMA-IR intotally thyroidectomized patientsrdquo Acta Clinica Belgica vol 61no 2 pp 69ndash73 2006

[60] P E Harris M Walker F Clark P D Home and K G MM Alberti ldquoForearm muscle metabolism in primary hypothy-roidismrdquo European Journal of Clinical Investigation vol 23 no9 pp 585ndash588 1993

[61] P W Ladenson P A Singer K B Ain et al ldquoAmerican thyroidassociation guidelines for detection of thyroid dysfunctionrdquoArchives of Internal Medicine vol 160 no 11 pp 1573ndash15752000

[62] H J Baskin R H Cobin D S Duick et al ldquoAmerican Associa-tion of Clinical Endocrinologists medical guidelines for clinicalpractice for the evaluation and treatment of hyperthyroidismand hypothyroidismrdquo Endocrine Practice vol 8 no 6 pp 457ndash469 2002

[63] ldquoUK guidelines for the use of thyroid function testsrdquo 2006httpwwwbritish-thyroid-associationorginfo-for-patientsDocsTFT guideline final version July 2006pdf

[64] S P Weinstein E OrsquoBoyle and R S Haber ldquoThyroid hormoneincreases basal and insulin-stimulated glucose transport inskeletal muscle the role of GLUT4 glucose transporter expres-sionrdquo Diabetes vol 43 no 10 pp 1185ndash1189 1994

[65] C N Mariash C H McSwigan and H C Towle ldquoGlucoseand triiodothyronine both induce malic enzyme in the rathepatocyte culture evidence that triiodothyronine multiplies aprimary glucose-generated signalrdquo Journal of Clinical Investiga-tion vol 68 no 6 pp 1485ndash1490 1981

[66] K Gauthier C Billon M Bissler et al ldquoThyroid hormonereceptor 120573(TR120573) and liver X receptor (LXR) regulate carbohy-drate-response element-binding protein (ChREBP) expression


in a tissue-selective mannerrdquo Journal of Biological Chemistryvol 285 no 36 pp 28156ndash28163 2010

[67] W Becker R Kluge T Kantner et al ldquoDifferential hepatic geneexpression in a polygenic mouse model with insulin resistanceand hyperglycemia evidence for a combined transcriptionaldysregulation of gluconeogenesis and fatty acid synthesisrdquoJournal of Molecular Endocrinology vol 32 no 1 pp 195ndash2082004

[68] G Brenta ldquoDiabetes and thyroid disordersrdquo British Journal ofDiabetes and Vascular Disease vol 10 no 4 pp 172ndash177 2010

[69] N Viguerie L Millet S Avizou H Vidal D Larrouy andD Langin ldquoRegulation of human adipocyte gene expressionby thyroid hormonerdquo Journal of Clinical Endocrinology andMetabolism vol 87 no 2 pp 630ndash634 2002

[70] L C Moeller A M Dumitrescu R L Walker P S Meltzerand S Refetoff ldquoThyroid hormone responsive genes in cul-tured human fibroblastsrdquo Journal of Clinical Endocrinology andMetabolism vol 90 no 2 pp 936ndash943 2005

[71] J MWeitzel C Radtke andH J Seitz ldquoTwo thyroid hormone-mediated gene expression patterns in vivo identified by cDNAexpression arrays in ratrdquo Nucleic Acids Research vol 29 no 24pp 5148ndash5155 2001

[72] P de Lange A Feola M Ragni et al ldquoDifferential 3531015840-triiodothyronine-mediated regulation of uncoupling protein 3transcription role of fatty acidsrdquo Endocrinology vol 148 no 8pp 4064ndash4072 2007

[73] R Senese V Valli M Moreno et al ldquoUncoupling protein 3expression levels influence insulin sensitivity fatty acid oxida-tion and related signaling pathwaysrdquo Pflugers Archiv EuropeanJournal of Physiology vol 461 no 1 pp 153ndash164 2011

[74] M Moreno E Silvestri R de Matteis et al ldquo3 5-Diiodo-L-thyronine prevents high-fat-diet-induced insulin resistance inrat skeletal muscle through metabolic and structural adapta-tionsrdquoThe FASEB Journal vol 25 no 10 pp 3312ndash3324 2011

[75] Y Tomer and F Menconi ldquoType 1 diabetes and autoimmunethyroiditis the genetic connectionrdquo Thyroid vol 19 no 2 pp99ndash102 2009

[76] F Menconi R Osman M C Monti D A Greenberg ES Concepcion and Y Tomer ldquoShared molecular amino acidsignature in the HLA-DR peptide binding pocket predisposesto both autoimmune diabetes and thyroiditisrdquoProceedings of theNational Academy of Sciences of theUnited States of America vol107 no 39 pp 16899ndash16903 2010

[77] P M Yen ldquoPhysiological and molecular basis of Thyroidhormone actionrdquo Physiological Reviews vol 81 no 3 pp 1097ndash1142 2001

[78] A Boelen ldquoThyroid hormones and glucose metabolism thestory begins before birthrdquo Experimental Physiology vol 94 no10 pp 1050ndash1051 2009

[79] L P Klieverik S F Janssen AVanRiel et al ldquoThyroid hormonemodulates glucose production via a sympathetic pathway fromthe hypothalamic paraventricular nucleus to the liverrdquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 106 no 14 pp 5966ndash5971 2009

[80] J M Dora W E Machado J Rheinheimer D Crispim andA L Maia ldquoAssociation of the type 2 deiodinase Thr92Alapolymorphism with type 2 diabetes case-control study andmeta-analysisrdquo European Journal of Endocrinology vol 163 no3 pp 427ndash434 2010

[81] A Chidakel D Mentuccia and F S Celi ldquoPeripheral metabo-lism of thyroid hormone and glucose homeostasisrdquoThyroid vol15 no 8 pp 899ndash903 2005

[82] E Maratou D J Hadjidakis A Kollias et al ldquoStudies ofinsulin resistance in patients with clinical and subclinicalhypothyroidismrdquo European Journal of Endocrinology vol 160no 5 pp 785ndash790 2009

[83] J A Chavez and S A Summers ldquoLipid oversupply selectiveinsulin resistance and lipotoxicity molecular mechanismsrdquoBiochimica et Biophysica Acta vol 1801 no 3 pp 252ndash265 2010

[84] M D Erion E E Cable B R Ito et al ldquoTargeting thyroid hor-mone receptor-120573 agonists to the liver reduces cholesterol andtriglycerides and improves the therapeutic indexrdquoProceedings ofthe National Academy of Sciences of the United States of Americavol 104 no 39 pp 15490ndash15495 2007

[85] C Cappelli M Rotondi I Pirola et al ldquoTSH-lowering effectof metformin in type 2 diabetic patients differences betweeneuthyroid untreated hypothyroid and euthyroid on L-T4 ther-apy patientsrdquo Diabetes Care vol 32 no 9 pp 1589ndash1590 2009

[86] RAVigerskyA Filmore-Nassar andARGlass ldquoThyrotropinsuppression by metforminrdquo The Journal of Clinical Endocrinol-ogy amp Metabolism vol 91 no 1 pp 225ndash227 2006

[87] C Cappelli M Rotondi I Pirola et al ldquoThyreotropin levels indiabetic patients on metformin treatmentrdquo European Journal ofEndocrinology vol 167 no 2 pp 261ndash265 2012

[88] G Chen S Xu K Renko and M Derwahl ldquoMetformininhibits growth of thyroid carcinoma cells suppresses self-renewal of derived cancer stem cells and potentiates the effectof chemotherapeutic agentsrdquo Journal of Clinical Endocrinologyamp Metabolism vol 97 no 4 pp E510ndashE520 2012

[89] J Klubo-Gwiezdzinska K Jensen J Costello et al ldquoMetformininhibits growth and decreases resistance to anoikis inmedullarythyroid cancer cellsrdquoEndocrine-RelatedCancer vol 19 no 3 pp447ndash456 2012


[91] P Webb ldquoSelective activators of thyroid hormone receptorsrdquoExpert Opinion on Investigational Drugs vol 13 no 5 pp 489ndash500 2004

[92] MMoreno P de Lange A Lombardi E Silvestri A Lanni andF Goglia ldquoMetabolic effects of thyroid hormone derivativesrdquoThyroid vol 18 no 2 pp 239ndash253 2008

[93] H A Yoshihara and T S Scanlan ldquoSelective thyroid hormonereceptor modulatorsrdquo Current Topics in Medicinal Chemistryvol 3 no 14 pp 1601ndash1616 2003


[95] M F Celani M E Bonati and N Stucci ldquoPrevalence ofabnormal thyrotropin concentrations measured by a sensitiveassay in patients with type 2 diabetes mellitusrdquo DiabetesResearch vol 27 no 1 pp 15ndash25 1994

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



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Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


uptake and upregulated hepatic glucose production alongwith dyslipidaemia which includes impaired homeostasis offatty acids triglycerides and lipoproteins [10]

2 Epidemiology

Thyroid dysfunction is a common endocrine disorder withvariable prevalence Wickham survey reveals that a preva-lence of thyroid dysfunction in male adults in England was66 [11] According to Colorado prevalence study 95 ofparticipants were found to have elevated thyroid-stimulatinghormone (TSH) while 22 had a low TSH Accordingto the National Health and Nutrition Examination Survey(NHANES III Study) hypothyroidism and hyperthyroidismwere reported in 46 and 13 of the total participants[12] respectively The prevalence of thyroid dysfunction isadvancing with age all over the world and frequency ofprevalence was higher in women than men The prevalenceof subclinical hypothyroidism is reported to be about 4 to 85percent and may be as high as 20 percent in women olderthan 60 years The prevalence of subclinical hyperthyroidismis reported to be approximately 2

The prevalence of thyroid disorder in diabetic populationwas reported to be 134 with higher prevalence (314) infemale T2DM patients as compared to (69) in male T2DMpatients [13]The prevalence of thyroid dysfunction in T2DMpatients was reported to be 123 in Greece and 16 in SaudiArabia byAkbar et al [14] Considerably T2DMpatientsweremore prone to thyroid disorders

3 Peripheral Effects of Thyroid Hormones onInsulin Secretion and Sensitivity

Thyroid hormones directly control insulin secretion In hy-pothyroidism there is a reduction in glucose-induced insulinsecretion by beta cells and the response of beta cells toglucose or catecholamine is increased in hyperthyroidismdueto increased beta cell mass Moreover insulin clearance isincreased in thyrotoxicosis [15 16]

31 Thyrotoxicosis Increased glucose output from liver is thepivotal reason for the induction of hyperinsulinaemia induc-tion of glucose intolerance and development of peripheralinsulin resistance [17] Glucose tolerance in thyrotoxicosis iscaused by elevated hepatic glucose output along with upregu-lated glycogenolysis [2] This phenomenon is responsible forworsening of subclinical diabetes and exaggeration of hyper-glycaemia in T2DMThyrotoxicosis may lead to ketoacidosisalso due to elevated lipolytic actions and increased hepatic120573 oxidation [18 19] This phenomenon has been shown inFigure 1

32 Hypothyroidism Reduced glucose absorption from gas-trointestinal tract accompanied by prolonged peripheral glu-cose accumulation gluconeogenesis diminished hepatic glu-cose output and reduced disposal of glucose are hallmarks ofhypothyroidism [20] In overt or subclinical hypothyroidism

Hyperthyroidism

LipolysisGLUT 2 on liver

Lactateproduction

Hyperglycemia

Nonoxidativeglucose disposal

Free fattyacids

Hepaticglucoseoutput

Figure 1The relation between hyperthyroidism and hyperglycemiavia lipid metabolism oxidative stress and hepatic dysfunction

Hyperthyroidism

Reduced insulin synthesis

Decreased

Delayedgluconeogenesis

Decreasedglucose disposal

hepaticglucoseoutput

Hypoglycemia

Impaired glucoseabsorption

Figure 2 The relation between hypothyroidism and hypoglycemiamediated by reduced insulin synthesis and impaired hepatic glucoseoutput

insulin resistance leads to glucose-stimulated insulin secre-tion [2] In subclinical hypothyroidism diminished rate ofinsulin stimulated glucose transport rate caused by perturbedexpression of glucose transporter type 2 gene (GLUT 2)translocation may lead to insulin resistance Moreover dueto reduced renal clearance of insulin in hypothyroid condi-tions physiological requirements of insulin were diminishedAnorectic conditions in hypothyroidism may also contributeto reduced insulin in this state An enhanced dose of insulinis required to ameliorate hypothyroidism but the therapywarrants caution for adrenal or pituitary failure [21] Thisphenomenon has been shown in Figure 2
































Lipogenesis




Malic enzymeChREBP

Protein kinase B



Increaselipolysis

Increaseglycolysis


GLUT 1 and 4


PGK and HIF



1120572

1120572


























9 Conclusion







Acknowledgment


References










































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of















































Lipogenesis




Malic enzymeChREBP

Protein kinase B



Increaselipolysis

Increaseglycolysis


GLUT 1 and 4


PGK and HIF



1120572

1120572


























9 Conclusion







Acknowledgment


References










































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of































9 Conclusion







Acknowledgment


References










































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






















































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















review article the relationship between type 2 diabetes … · 2019. 7. 31. · tion of glucose...

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